Cyclohexyloxy-substituted heterocyclics, medicines containing these compounds and method for the production thereof

ABSTRACT

The present invention relates to cyclohexyloxy-substituted heterocycles of general formula (I) 
                         
the tautomers, the stereoisomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids, which have valuable pharmacological properties, particularly an inhibitory effect on signal transduction mediated by tyrosine kinases, the use thereof for the treatment of diseases, particularly tumoral diseases as well as benign prostatic hyperplasia (BPH), diseases of the lungs and airways and the preparation thereof.

The present invention relates to cyclohexyloxy-substituted heterocyclesof general formula

the tautomers, the stereoisomers, the mixtures thereof and the saltsthereof, particularly the physiologically acceptable salts thereof withinorganic or organic acids, which have valuable pharmacologicalproperties, particularly an inhibitory effect on signal transductionmediated by tyrosine kinases, the use thereof for the treatment ofdiseases, particularly tumoral diseases as well as benign prostatichyperplasia (BPH), diseases of the lungs and airways and the preparationthereof.

The problem of the present invention is to prepare new compounds whichon the basis of their pharmaceutical effectiveness as tyrosine-kinaseinhibitors, may be used therapeutically, i.e. for the treatment ofpathophysiological processes caused by hyperfunction of tyrosinekinases.

DETAILED DESCRIPTION OF THE INVENTION

It has surprisingly been found that the problem mentioned above issolved by compounds of formula (I), wherein the group R^(a) has themeanings given hereinafter.

The present invention therefore relates to compounds of general formula(I),

whereinR^(a) denotes an ethyl, propyl, butyl, cyclopropyl, cyclopropylmethyl,cyclobutyl, cyclobutylmethyl, 3-tetrahydrofuranyl,tetrahydrofuranylmethyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl andtetrahydropyranylmethyl group, and wherein, unless stated otherwise, theabove-mentioned alkyl groups may be straight-chain or branched,optionally in the form of the tautomers, the racemates, the enantiomers,the diastereomers and the mixtures thereof, and optionally thepharmacologically acceptable acid addition salts thereof, and thesolvates and hydrates thereof.

Preferred compounds of formula (I) are those wherein

R^(a) denotes a group selected from among ethyl, butyl,cyclopropylmethyl and 4-tetrahydropyranyl group,

optionally in the form of the tautomers, the racemates, the enantiomers,the diastereomers and the mixtures thereof, and optionally thepharmacologically acceptable acid addition salts thereof, the solvatesand hydrates thereof.

The invention also relates to compounds of formula (I) for use asmedicaments. Preferably the compounds of formula (I) are used in casesof inflammatory or allergic diseases of the airways.

The compounds of formula (I) are particularly preferably used in casesof a disease selected from among chronic bronchitis, acute bronchitis,bronchitis caused by bacterial or viral infection or fungi or helminths,allergic bronchitis, toxic bronchitis, chronic obstructive bronchitis(COPD), asthma (intrinsic or allergic), paediatric asthma,bronchiectasis, allergic alveolitis, allergic or non-allergic rhinitis,chronic sinusitis, cystic fibrosis or mucoviscidosis,alpha-1-antitrypsin deficiency, cough, pulmonary emphysema, interstitiallung diseases, alveolitis, hyperreactive airways, nasal polyps,pulmonary oedema, pneumonitis of different origins, e.g.radiation-induced or caused by aspiration or infectious pneumonitis,collagenoses such as lupus erythematodes, systemic sclerodermy,sarcoidosis and Boeck's disease.

It is also particularly preferred to use the compounds of formula (I) incases of inflammatory or allergic complaints in which autoimmunereactions are involved. It is also particularly preferred to use thecompounds of formula (I) in cases of a disease in the form of benign ormalignant tumours.

The invention further relates to a pharmaceutical formulation containinga compound of formula (I).

Preferably an orally administered pharmaceutical formulation containinga compound of formula (I) is used.

The invention further relates to medicament combinations which contain,besides one or more compounds of formula (I), as further activesubstances, one or more compounds selected from among the categories ofbetamimetics, anticholinergics, corticosteroids, furtherPDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, dopamine agonists,H1-antihistamines, PAF-antagonists and PI3-kinase inhibitors or doubleor triple combinations thereof.

Examples of betamimetics which may be used here preferably includecompounds which are selected from among arformoterol, carmoterol,formoterol, indacaterol, salmeterol, albuterol, bambuterol, bitolterol,broxaterol, carbuterol, clenbuterol, fenoterol, hexoprenalin, ibuterol,isoetharin, isoprenalin, levosalbutamol, mabuterol, meluadrin,metaproterenol, milveterol, orciprenalin, pirbuterol, procaterol,reproterol, rimiterol, ritodrin, salmefamol, soterenol, sulphonterol,terbutalin, tiaramid, tolubuterol, zinterol and

-   6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one-   8-{2-[2-(2,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one-   8-{2-[2-(3,5-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one-   8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one-   8-{2-[2-(4-fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one-   N-(5-{2-[3-(4,4-diethyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-1,1-dimethyl-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methanesulphonamide-   N-(5-{2-[3-(4,4-diethyl-6-fluoro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-1,1-dimethyl-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methanesulphonamide-   N-(5-{2-[3-(4,4-diethyl-6-methoxy-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-1,1-dimethyl-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methanesulphonamide-   N-(5-{2-[1,1-dimethyl-3-(2-oxo-4,4-dipropyl-4H-benzo[d][1,3]oxazin-1-yl)-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methanesulphonamide-   8-{2-[1,1-dimethyl-3-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one-   8-{2-[1,1-dimethyl-3-(6-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one-   8-{2-[1,1-dimethyl-3-(2-oxo-5-trifluoromethyl-2,3-dihydro-benzoimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one-   8-{2-[1,1-dimethyl-3-(3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    N-[2-hydroxy-5-((1R)-1-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]-ethylamino}-ethyl)-phenyl]-formamide-   8-hydroxy-5-((1R)-1-hydroxy-2-{2-[4-(6-methoxy-biphenyl-3-ylamino)-phenyl]-ethylamino}-ethyl)-1H-quinolin-2-one-   8-hydroxy-5-[(1R)-1-hydroxy-2-(6-phenethylamino-hexylamino)-ethyl]-1H-quinolin-2-one-   5-[(1R)-2-(2-{4-[4-(2-amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one-   [3-(4-{6-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-5-methyl-phenyl]-urea-   4-((1R)-2-{6-[2-(2,6-dichloro-benzyloxy)-ethoxy]-hexylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenol-   3-(4-{6-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulphonamide-   3-(3-{7-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-heptyloxy}-propyl)-benzenesulphonamide-   4-((1R)-2-{6-[4-(3-cyclopentanesulphonyl-phenyl)-butoxy]-hexylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenol-   N-1-adamantanyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide-   (1R)-5-{2-[6-(2,2-difluoro-2-phenyl-ethoxy)-hexylamino]-1-hydroxy-ethyl}-8-hydroxy-1H-quinolin-2-one-   (R,S)-4-(2-{[6-(2,2-difluoro-4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol-   (R,S)-4-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol-   (R,S)-4-(2-{[4,4-difluoro-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol-   (R,S)-4-(2-{[6-(4,4-difluoro-4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol-   (R,S)-5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-8-hydroxyquinolin-2(1H)-one-   (R,S)-[2-({6-[2,2-difluoro-2-(3-methylphenyl)ethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol-   4-(1R)-2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol-   (R,S)-2-(hydroxymethyl)-4-(1-hydroxy-2-{[4,4,5l5-tetrafluoro-6-(3-phenylpropoxy)-hexyl]amino}ethyl)phenol-   (R,S)-[5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-2-hydroxyphenyl]formamide-   (R,S)-4-[2-({6-[2-(3-bromophenyl)-2,2-difluoroethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol-   (R,S)—N-[3-(1,1-difluoro-2-{[6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]-ethyl}amino)hexyl]oxy}ethyl)phenyl]-urea-   3-[3-(1,1-difluoro-2-{[6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}ethyl)phenyl]imidazolidin-2,4-dione-   (R,S)-4-[2-({6-[2,2-difluoro-2-(3-methoxyphenyl)ethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol-   5-((1R)-2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one-   4-((1R)-2-{[4,4-difluoro-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol-   (R,S)-4-(2-{[6-(3,3-difluoro-3-phenylpropoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol-   (R,S)-(2-{[6-(2,2-difluoro-2-phenylethoxy)-4,4-difluorohexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol-   (R,S)-4-(2-{[6-(2,2-difluoro-3-phenylpropoxy)hexyl]amino}-1-hydroxy    ethyl)-2-(hydroxymethyl)phenol-   3-[2-(3-chloro-phenyl)-ethoxy]-N-(2-diethylamino-ethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-ethyl}-propionamide-   N-(2-diethylamino-ethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-ethyl}-3-(2-naphthalen-1-yl-ethoxy)-propionamide-   7-[2-(2-{3-[2-(2-chloro-phenyl)-ethylamino]-propylsulphanyl}-ethylamino)-1-hydroxy-ethyl]-4-hydroxy-3H-benzothiazol-2-one    optionally in the form of the racemates, enantiomers, diastereomers    and optionally in the form of the pharmacologically acceptable acid    addition salts, solvates or hydrates thereof. Preferably, according    to the invention, the acid addition salts of the betamimetics are    selected from among the hydrochloride, hydrobromide, hydriodide,    hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate,    hydromaleate, hydroacetate, hydrocitrate, hydrofumarate,    hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and    hydro-p-toluenesulphonate.

Examples of anticholinergics which may be used here preferably includecompounds which are selected from among: tiotropium salts, preferablythe bromide salt, oxitropium salts, preferably the bromide salt,flutropium salts, preferably the bromide salt, ipratropium salts,preferably the bromide salt, aclidinium salts, preferably the bromidesalt, glycopyrronium salts, preferably the bromide salt, trospium salts,preferably the chloride salt, tolterodine,(3R)-1-phenethyl-3-(9H-xanthen-9-carbonyloxy)-1-azoniabicyclo[2,2,2]octane-salts.In the above-mentioned salts the cations are the pharmacologicallyactive constituents. As X⁻ anions the above-mentioned salts maypreferably contain chloride, bromide, iodide, sulphate, phosphate,methanesulphonate, nitrate, maleate, acetate, citrate, fumarate,tartrate, oxalate, succinate, benzoate or p-toluenesulphonate, whilechloride, bromide, iodide, sulphate, methanesulphonate orp-toluenesulphonate are preferred as counter-ions. Of all the salts thechlorides, bromides, iodides and methanesulphonates are particularlypreferred.

Other specified compounds are:

-   tropenol 2,2-diphenylpropionate methobromide,-   scopine 2,2-diphenylpropionate methobromide,-   scopine 2-fluoro-2,2-diphenylacetate methobromide,-   tropenol 2-fluoro-2,2-diphenylacetate methobromide,-   tropenol 3,3′,4,4′-tetrafluorobenzilate methobromide,-   scopine 3,3′,4,4′-tetrafluorobenzilate methobromide,-   tropenol 4,4′-difluorobenzilate methobromide,-   scopine 4,4′-difluorobenzilate methobromide,-   tropenol 3,3′-difluorobenzilate methobromide,-   scopine 3,3′-difluorobenzilate methobromide;-   tropenol 9-hydroxy-fluorene-9-carboxylate methobromide,-   tropenol 9-fluoro-fluorene-9-carboxylate methobromide,-   scopine 9-hydroxy-fluorene-9-carboxylate methobromide,-   scopine 9-fluoro-fluorene-9-carboxylate methobromide;-   tropenol 9-methyl-fluorene-9-carboxylate methobromide,-   scopine 9-methyl-fluorene-9-carboxylate methobromide,-   cyclopropyltropine benzilate methobromide,-   cyclopropyltropine 2,2-diphenylpropionate methobromide,-   cyclopropyltropine 9-hydroxy-xanthene-9-carboxylate methobromide,-   cyclopropyltropine 9-methyl-fluorene-9-carboxylate methobromide,-   cyclopropyltropine 9-methyl-xanthene-9-carboxylate methobromide,-   cyclopropyltropine 9-hydroxy-fluorene-9-carboxylate methobromide,-   cyclopropyltropine methyl 4,4′-difluorobenzilate methobromide,-   tropenol 9-hydroxy-xanthene-9-carboxylate methobromide,-   scopine 9-hydroxy-xanthene-9-carboxylate methobromide,-   tropenol 9-methyl-xanthene-9-carboxylate-methobromide,-   scopine 9-methyl-xanthene-9-carboxylate-methobromide,-   tropenol 9-ethyl-xanthene-9-carboxylate methobromide,-   tropenol 9-difluoromethyl-xanthene-9-carboxylate methobromide,-   scopine 9-hydroxymethyl-xanthene-9-carboxylate methobromide.    The above-mentioned compounds may also be used as salts within the    scope of the present invention, while instead of the methobromide,    the metho-X salts may be used wherein X may have the meanings given    hereinbefore for X⁻.

Compounds which may be used as corticosteroids are preferably thoseselected from among beclomethasone, betamethasone, budesonide,butixocort, ciclesonide, deflazacort, dexamethasone, etiprednol,flunisolide, fluticasone, loteprednol, mometasone, prednisolone,prednisone, rofleponide, triamcinolone, tipredane and

-   pregna-1,4-diene-3,20-dione,    6-fluoro-1-hydroxy-16,17-[(1-methylethylidene)bis(oxy)]-21-[[4-[(nitrooxy)methyl]benzoyl]oxy]-,    (6-alpha,11-beta,16-alpha)-(9Cl) (NCX-1024),-   16,17-butylidenedioxy-6,9-difluoro-11-hydroxy-17-(methylthio)androst-4-en-3-one    (RPR-106541),-   (S)-fluoromethyl    6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionate,-   (S)-(2-oxo-tetrahydro-furan-3S-yl)    6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-dien-17-carbothionate,-   cyanomethyl    6-alpha,9-alpha-difluoro-11-beta-hydroxy-16alpha-methyl-3-oxo-17alpha-(2,2,3,3-tetramethylcyclopropylcarbonyl)oxy-androsta-1,4-diene-17beta-carboxylate,    optionally in the form of the racemates, enantiomers or    diastereomers thereof and optionally in the form of the salts and    derivatives thereof, the solvates and/or hydrates thereof. Any    reference to steroids includes a reference to any salts or    derivatives, hydrates or solvates thereof which may exist. Examples    of possible salts and derivatives of the steroids may be: alkali    metal salts, such as for example sodium or potassium salts,    sulphobenzoates, phosphates, isonicotinates, acetates,    dichloroacetates, propionates, dihydrogen phosphates, palmitates,    pivalates or furoates.

PDE4-inhibitors which may be used are preferably compounds selected fromamong enprofyllin, theophyllin, roflumilast, ariflo (cilomilast),tofimilast, pumafentrin, lirimilast, apremilast, arofyllin, atizoram,oglemilastum, tetomilast, and

-   5-[(N-(2,5-dichloro-3-pyridinyl)-carboxamide]-8-methoxy-quinoline    (D-4418),-   N-(3,5-dichloro-1-oxido-4-pyridinyl)-carboxamide]-8-methoxy-2-(trifluoromethyl)-quinoline    (D-4396 (Sch-351591)),    N-(3,5-dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indol-3-yl]glyoxylic    acid amide (AWD-12-281 (GW-842470)),    9-[(2-fluorophenyl)methyl]-N-methyl-2-(trifluoromethyl)-9H-purin-6-amine    (NCS-613),-   4-[(2R)-2-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-phenylethyl]-pyridine    (CDP-840),-   N-[(3R)-3,4,6,7-tetrahydro-9-methyl-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]benzodiazepin-3-yl]-4-pyridinecarboxamide    (PD-168787),-   4-[6,7-diethoxy-2,3-bis(hydroxymethyl)-1-naphthalenyl]-1-(2-methoxyethyl)-2(1H)-pyridinone    (T-440),-   2-[4-[6,7-diethoxy-2,3-bis(hydroxymethyl)-1-naphthalenyl]-2-pyridinyl]-4-(3-pyridinyl)-1(2H)-phthalazinone    (T-2585),-   (3-(3-cyclopenyloxy-4-methoxybenzyl)-6-ethylamino-8-isopropyl-3H-purine    (V-11294A),-   beta-[3-(cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide    (CDC-801),-   imidazo[1,5-a]pyrido[3,2-e]pyrazin-6(5H)-one,    9-ethyl-2-methoxy-7-methyl-5-propyl-(D-22888),-   5-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-[(3-methylphenyl)methyl],    (3S,5S)-2-piperidinone (HT-0712),-   4-[1-[3,4-bis(difluoromethoxy)phenyl]-2-(3-methyl-1-oxido-4-pyridinylethyl]-alpha,alpha-bis(trifluoromethyl)-benzenemethanol    (L-826141),-   N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide,-   (−)p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide,-   (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone,-   3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N′-[N-2-cyano-5-methyl-isothioureido]benzyl)-2-pyrrolidone,-   cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic    acid],-   2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one,-   cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol],-   (R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate,-   (S)-(−)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate,-   9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine,-   9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine,    optionally in the form of the racemates, enantiomers, diastereomers    thereof and optionally in the form of the pharmacologically    acceptable acid addition salts, solvates or hydrates thereof.    According to the invention the preferred acid addition salts are    selected from among hydrochloride, hydrobromide, hydriodide,    hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate,    hydromaleate, hydroacetate, hydrocitrate, hydrofumarate,    hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and    hydro-p-toluenesulphonate.

EGFR inhibitors which may be used are preferably compounds selected fromamong cetuximab, trastuzumab, panitumumab (=ABX-EGF), Mab ICR-62,gefitinib, canertinib, erlotinib, and

-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,-   4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,-   4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,-   4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,-   4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,-   4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline,-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline,-   4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline,-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,-   4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline,-   4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinylcarbonyl)amino]-quinazoline,-   4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine-   3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline,-   4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulphonyl-ethyl)amino]methyl}-furan-2-yl)quinazoline,-   4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,-   4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,-   4-[(3-ethynyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonylamino-ethoxy)-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethansulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,-   4-[(3-ethynyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,-   4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline,-   4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline,-   4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,-   4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,-   4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline,-   4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,-   4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline,-   3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline;-   [4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-7-(2-{4-[(S)-(2-oxo-tetrahydrofuran-5-yl)carbonyl]-piperazin-1-yl}-ethoxy)-6-[(vinylcarbonyl)amino]-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-6-[(vinylcarbonyl)amino]-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-7-[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-butyloxy]-6-[(vinylcarbonyl)amino]-quinazoline,-   4-[(3-chloro-4-fluoro-phenyl)amino]-7-[4-((S)-6-methyl-2-oxo-morpholin-4-yl)-butyloxy]-6-[(vinylcarbonyl)amino]-quinazoline,    and-   4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{N-[2-(ethoxycarbonyl)-ethyl]-N-[(ethoxycarbonyl)methyl]amino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxy-quinazoline,    optionally in the form of the racemates, enantiomers or    diastereomers thereof and optionally in the form of the    pharmacologically acceptable acid addition salts, solvates and/or    hydrates thereof. According to the invention the preferred acid    addition salts are selected from among hydrochloride, hydrobromide,    hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate,    hydronitrate, hydromaleate, hydroacetate, hydrocitrate,    hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate,    hydrobenzoate and hydro-p-toluenesulphonate.

LTD4-receptor antagonists used here are preferably compounds selectedfrom among montelukast, pranlukast, zafirlukast, and(E)-8-[2-[4-[4-(4-fluorophenyl)butoxy]phenyl]ethenyl]-2-(1H-tetrazol-5-yl)-4H-1-benzopyran-4-one(MEN-91507),

-   4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyric    acid (MN-001),    1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methylcyclopropaneacetic    acid,    1-(((1(R)-3(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic    acid,    [2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic    acid optionally in the form of the    racemates, enantiomers, diastereomers thereof and optionally in the    form of the pharmacologically acceptable acid addition salts,    solvates or hydrates thereof. According to the invention the    preferred acid addition salts are selected from among hydrochloride,    hydrobromide, hydriodide, hydrosulphate, hydrophosphate,    hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,    hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate,    hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate. By    salts or derivatives which the LTD4-receptor antagonists are    optionally capable of forming are meant, for example: alkali metal    salts, such as for example sodium or potassium salts, alkaline earth    metal salts, sulphobenzoates, phosphates, isonicotinates, acetates,    propionates, dihydrogen phosphates, palmitates, pivalates or    furoates.

Histamine H1 receptor antagonists which may be used are preferablycompounds selected from among epinastine, cetirizine, azelastine,fexofenadine, levocabastine, loratadine, mizolastine, ketotifen,emedastine, dimetindene, clemastine, bamipine, cexchlorpheniramine,pheniramine, doxylamine, chlorphenoxamine, dimenhydrinate,diphenhydramine, promethazine, ebastine, olopatadine, desloratidine andmeclozine, optionally in the form of the racemates, enantiomers,diastereomers thereof and optionally in the form of thepharmacologically acceptable acid addition salts, solvates or hydratesthereof. According to the invention these acid addition salts arepreferably selected from among the hydrochloride, hydrobromide,hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate,hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate,hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate andhydro-p-toluenesulphonate.

Examples of PAF-antagonists preferably include compounds selected fromamong lexipafant and4-(2-chlorophenyl)-9-methyl-2-[3(4-morpholinyl)-3-propanon-1-yl]-6H-thieno-[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepine

-   6-(2-chlorophenyl)-8,9-dihydro-1-methyl-8-[(4-morpholinyhcarbonyl]-4H,7H-cyclo-penta-[4,5]thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine,    optionally in the form of the racemates, enantiomers, diastereomers    thereof and optionally in the form of the pharmacologically    acceptable acid addition salts, solvates or hydrates thereof.    Preferred acid addition salts according to the invention are    selected from among hydrochloride, hydrobromide, hydriodide,    hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate,    hydromaleate, hydroacetate, hydrocitrate, hydrofumarate,    hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and    hydro-p-toluenesulphonate.

The dopamine receptor agonists used are preferably compounds selectedfrom among bromocriptine, cabergoline, alpha-dihydroergocryptine,lisuride, pergolide, pramipexole, roxindole, ropinirole, talipexole,terguride and viozan, optionally in the form of the racemates,enantiomers, diastereomers thereof and optionally in the form of thepharmacologically acceptable acid addition salts, solvates or hydratesthereof. According to the invention these acid addition salts arepreferably selected from among the hydrochloride, hydrobromide,hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate,hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate,hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate andhydro-p-toluenesulphonate.

Examples of substances of preferred PI3 kinase antagonists that may beused are preferably compounds selected from among

-   5-(quinoxalin-6-ylmethylene)thiazolidine-2,4-dione (AS-605240),-   2-[(6-amino-9H-purin-9-yl)methyl]-5-methyl-3-(2-methylphenyl)-4(3H)-quinazolinone    (C-87114),-   2-methyl-2-[4-[3-methyl-2-oxo-8-(quinoline-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile    (BEZ-235),    optionally in the form of the racemates, enantiomers, diastereomers    thereof and optionally in the form of the pharmacologically    acceptable acid addition salts, prodrugs, solvates or hydrates    thereof.

TERMS AND DEFINITIONS USED

By the term “optionally substituted” is meant within the scope of theinvention the above-mentioned group, optionally substituted by alower-molecular group. Examples of lower-molecular groups regarded aschemically meaningful are groups consisting of 1-25 atoms.

Preferably such groups have no negative effect on the pharmacologicalefficacy of the compounds.

For example the groups may comprise:

-   -   Straight-chain or branched carbon chains, optionally interrupted        by heteroatoms, optionally substituted by rings, heteroatoms or        other common functional groups.    -   Aromatic or non-aromatic ring systems consisting of carbon atoms        and optionally heteroatoms, which may in turn be substituted by        functional groups.    -   A number of aromatic or non-aromatic ring systems consisting of        carbon atoms and optionally heteroatoms which may be linked by        one or more carbon chains, optionally interrupted by        heteroatoms, optionally substituted by heteroatoms or other        common functional groups.

Also included in the subject-matter of this invention are the compoundsaccording to the invention, including the salts thereof, wherein one ormore hydrogen atoms, for example one, two, three, four or five hydrogenatoms, are replaced by deuterium.

Where a hyphen open on one side “-” is used in the structural formula ofa substituent, this hyphen is to be understood as the linkage point tothe remainder of the molecule. The substituent replaces thecorresponding groups R^(a), R^(b), etc. If no hyphen open on one side isused in the structural formula of a substituent, the linkage point tothe remainder of the molecule is clear from the structural formulaitself.

Compounds of general formula (I) may contain acid groups, primarilycarboxyl groups, and/or basic groups such as e.g. amino functions.Compounds of general formula (I) may therefore be present as internalsalts, as salts with pharmaceutically useable inorganic acids such ashydrochloric acid, sulphuric acid, phosphoric acid, sulphonic acid ororganic acids (such as for example maleic acid, fumaric acid, citricacid, tartaric acid or acetic acid) or as salts with pharmaceuticallyuseable bases such as alkali metal or alkaline earth metal hydroxides orcarbonates, zinc or ammonium hydroxides or organic amines such as e.g.diethylamine, triethylamine, triethanolamine, inter alia. For preparingthe alkali metal and alkaline earth metal salts of the compound offormula (I), it is preferable to use the alkali metal and alkaline earthmetal hydroxides and hydrides, while the hydroxides and hydrides of thealkali metals, particularly sodium and potassium are preferred, andsodium and potassium hydroxide are particularly preferred. (See alsoPharmaceutical Salts, S. M. Birge et al., J. Pharm. Sci. (1977), 66,1-19)

As already mentioned, the compounds of general formula (I) may beconverted into the salts thereof, particularly for pharmaceutical use,into the pharmacologically acceptable acid addition salts thereof withan inorganic or organic acid. Suitable acids for this purpose includefor example succinic acid, hydrobromic acid, acetic acid, fumaric acid,maleic acid, methanesulphonic acid, lactic acid, phosphoric acid,hydrochloric acid, sulphuric acid, tartaric acid or citric acid. Inaddition, mixtures of the above-mentioned acids may be used.

The present invention relates to the respective compounds, optionally inthe form of the individual diastereomers, mixtures of the individualdiastereomers and/or individual enantiomers, mixtures of the individualenantiomers or racemates thereof, in the form of the tautomers as wellas in the form of the free bases or the corresponding acid additionsalts with pharmacologically acceptable acids—such as for example acidaddition salts with hydrohalic acids—for example hydrochloric orhydrobromic acid or organic acids—such as for example tartaric acid,fumaric acid, citric acid or methanesulphonic acid.

“Protective groups” for the purposes of the present invention is acollective term for organic groups with which certain functional groupsof a molecule containing a number of active centres can temporarily beprotected from attack by reagents so that reactions take place only atthe desired (unprotected) sites. The protective groups should beintroduced selectively under mild conditions. They must be stable forthe duration of the protection under all the conditions of the reactionsand purifying procedures which are to be carried out; racemisations andepimerisations must be suppressed. Protective groups should be capableof being cleaved again under mild conditions selectively and ideally inhigh yields. The choice of a suitable protective group, the reactionconditions (solvent, temperature, duration, etc.), and also the optionsfor removing a protective group are known in the art (e.g. PhilipKocienski, Protecting Groups, 3rd ed. 2004, THIEME, Stuttgart, ISBN:3131370033).

By an “organic solvent” is meant, within the scope of the invention, anorganic, low-molecular substance which can dissolve other organicsubstances by a physical method. To be suitable the prerequisite for thesolvent is that neither the dissolving substance nor the dissolvedsubstance should be chemically altered during the dissolving process,i.e. the components of the solution should be recoverable in theiroriginal form by physical separation processes such as distillation,crystallisation, sublimation, evaporation or adsorption. For variousreasons, not only the pure solvents but also mixtures that combine thedissolving properties may be used. Examples include:

-   -   alcohols, preferably methanol, ethanol, propanol, butanol,        octanol, cyclohexanol;    -   glycols, preferably ethyleneglycol, diethyleneglycol;    -   ethers/glycolethers, preferably diethyl ether,        tert-butyl-methylether, dibutylether, anisole, dioxane,        tetrahydrofuran, mono-, di-, tri-, polyethyleneglycol ethers;    -   ketones, preferably acetone, butanone, cyclohexanone;    -   esters, preferably acetic acid esters, glycolesters;    -   amides and other nitrogen compounds, preferably        dimethylformamide, pyridine, N-methylpyrrolidone,    -   acetonitrile;    -   sulphur compounds, preferably carbon disulphide,        dimethylsulphoxide, sulpholane;    -   nitro compounds, preferably nitrobenzene;    -   halogenated hydrocarbons, preferably dichloromethane,        chloroform, tetrachlormethane, tri- and tetrachloroethene,        1,2-dichloroethane, chlorofluorocarbons;    -   aliphatic or alicyclic hydrocarbons, preferably benzines,        petroleum ether, cyclohexane, methylcyclohexane, decaline,        terpene-L; or    -   aromatic hydrocarbons, preferably benzene, toluene, o-xylene,        m-xylene, p-xylene; or corresponding mixtures thereof.

The term diastereomerically pure describes within the scope of thepresent invention compounds of formula (I), which are present in adiastereomeric purity of at least 85% de, preferably at least 90% de,particularly preferably >95% de. The term de (diastereomeric excess) isknown in the art and describes the optical purity of diastereomericcompounds.

The term enantiomerically pure describes within the scope of the presentinvention compounds of formula (I), which are present in anenantiomerical purity of at least 85% ee, preferably at least 90% ee,particularly preferably >95% ee. The term ee (enantiomeric excess) isknown in the art and describes the optical purity of chiral compounds.

By the term “C₁₋₆-alkyl” (including those which are part of othergroups) are meant branched and unbranched alkyl groups with 1 to 6carbon atoms and by the term “C₁₋₄-alkyl” are meant branched andunbranched alkyl groups with 1 to 4 carbon atoms. Preferred are alkylgroups with 1 to 4 carbon atoms, particularly preferably alkyl groupswith 1 to 2 carbon atoms. Examples include: methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl,iso-pentyl, neo-pentyl or hexyl. The abbreviations Me, Et, n-Pr, i-Pr,n-Bu, i-Bu, t-Bu, etc. may optionally also be used for theabove-mentioned groups. Unless stated otherwise, the definitions propyl,butyl, pentyl and hexyl include all the possible isomeric forms of thegroups in question. Thus, for example, propyl includes n-propyl andiso-propyl, butyl includes iso-butyl, sec-butyl and tert-butyl etc.

By the term “C₃₋₇-cycloalkyl” (including those which are part of othergroups) are meant cyclic alkyl groups with 3 or 7 carbon atoms. Examplesinclude: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl orcycloheptyl. Unless otherwise stated, the cyclic alkyl groups may besubstituted by one or more groups selected from among methyl, ethyl,iso-propyl, tert-butyl, hydroxy and fluorine.

By the term “aryl” (including those which are part of other groups) aremeant aromatic ring systems with 6, 10 or 14 carbon atoms. Examplesinclude: phenyl, naphthyl, anthracenyl or phenanthrenyl, the preferredaryl group being phenyl.

“Halogen” within the scope of the present invention denotes fluorine,chlorine, bromine or iodine. Unless stated to the contrary, fluorine,chlorine and bromine are regarded as preferred halogens.

Methods of Preparation

The following methods are suitable, for example, for preparing compoundsof general formula (I):

a) reacting a compound of general formula

with a compound of general formula

whereinR^(a) is as hereinbefore defined and Z¹ denotes a leaving group such asa halogen atom, e.g. a chlorine or bromine atom, a sulphonyloxy groupsuch as a methanesulphonyloxy or p-toluenesulphonyloxy group or ahydroxy group.

With a compound of general formula (III), wherein Z¹ denotes a halogenatom or a sulphonyloxy group, the reaction is expediently carried out ina solvent such as ethanol, isopropanol, acetonitrile, toluene,tetrahydrofuran, dioxane, dimethylformamide, dimethylsulphoxide orN-methylpyrrolidinone, preferably in the presence of a base such aspotassium carbonate, potassium-tert-butoxide, sodium hydride orN-ethyl-diisopropylamine, at temperatures in the range from 20° C. to160° C., for example at temperatures in the range from 60° C. to 140° C.

With a compound of general formula III wherein Z¹ denotes a hydroxygroup, the reaction is carried out in the presence of a dehydratingagent, preferably in the presence of a phosphine and an azodicarboxylicacid derivative such as e.g. triphenylphosphine/diethylazodicarboxylate, conveniently in a solvent such as methylene chloride,acetonitrile, tetrahydrofuran, dioxane, toluene or ethyleneglycoldiethylether at temperatures between −50 and 150° C., but preferably attemperatures between −20 and 80° C.

b) reacting a compound of general formula (IV)

wherein R^(a) is as hereinbefore defined, with a halogenating agent, forexample an acid halide such as thionyl chloride, thionyl bromide,phosphorus trichloride, phosphorus pentachloride, phosphorusoxychloride, or triphenylphosphine/carbon tetrachloride ortriphenylphosphine/N-chlorosuccinimide to obtain an intermediatecompound of general formula (V),

wherein R^(a) is as hereinbefore defined and Z² denotes a halogen atomsuch as a chlorine or bromine atom,and subsequent reaction with a compound of general formula (VI),

or the salts thereof.

The reaction with the halogenating agent is optionally carried out in asolvent such as methylene chloride, chloroform, acetonitrile or tolueneand optionally in the presence of a base such as N,N-diethylaniline,triethylamine or N-ethyl-diisopropylamine at temperatures in the rangefrom 20° C. to 160° C., preferably from 40° C. to 120° C. Preferably,however, the reaction is carried out with thionyl chloride and catalyticamounts of dimethylformamide at the boiling temperature of the reactionmixture or with phosphorus oxychloride in acetonitrile in the presenceof triethylamine at the boiling temperature of the reaction mixture orwith triphenylphosphine/carbon tetrachloride or withtriphenylphosphine/N-chlorosuccinimide in acetonitrile.

The reaction of the compound of general formula (VI) with the compoundof general formula (VII) or the salts thereof is conveniently carriedout in a solvent such as ethanol, isopropanol, acetonitrile, dioxane ordimethylformamide, optionally in the presence of a base such aspotassium carbonate, triethylamine or N-ethyl-diisopropylamine, attemperatures in the range from 20° C. and 160° C., preferably from 60°C. to 120° C. However, the reaction is preferably carried out inisopropanol at the boiling temperature of the reaction mixture.

The reaction of a compound of general formula (V) to obtain a compoundof general formula (I) may also be carried out as a one-pot reaction,for example in acetonitrile in the presence of triethylamine.

c) reacting a compound of general formula

with a compound of general formulaH—R^(a),  (VIII)whereinR^(a) is as hereinbefore defined, in the presence of a reducing agent.

The reductive amination is carried out for example in a solvent such asdichloromethane, 1,2-dichloroethane, methanol, ethanol, tetrahydrofuranor dioxane in the presence of a reducing agent such as sodiumtriacetoxyborohydride or sodium cyanoborohydride, optionally in thepresence of acetic acid at temperatures between 0° C. and 80° C. Thereductive amination may also be carried out with hydrogen in thepresence of a catalyst such as palladium on activated charcoal orplatinum oxide. Another possibility is to form the enamine from theketone of general formula VII and the amine of general formula VIIIwhile cleaving hydrogen, for example with titanium (IV)-isopropoxide,and then to reduce this, for example with sodium borohydride orhydrogen/palladium on activated charcoal.

In the reactions described hereinbefore any reactive groups present suchas hydroxy, amino, alkylamino or imino groups may be protected duringthe reaction by conventional protective groups which are cleaved againafter the reaction.

For example a protecting group for a hydroxy group might be thetrimethylsilyl, acetyl, trityl, benzyl or tetrahydropyranyl group.

Protecting groups for an amino, alkylamino or imino group might be, forexample, the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl,tert.-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or2,4-dimethoxybenzyl group.

Any protective group used is optionally subsequently cleaved for exampleby hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water,acetic acid/water, tetrahydrofuran/water or dioxane/water, in thepresence of an acid such as trifluoroacetic acid, hydrochloric acid orsulphuric acid or in the presence of an alkali metal base such as sodiumhydroxide or potassium hydroxide or aprotically, e.g. in the presence ofiodotrimethylsilane, at temperatures between 0 and 120° C., preferablyat temperatures between 10 and 100° C.

A benzyl, methoxybenzyl or benzyloxycarbonyl group, however, is cleavedby hydrogenolysis, for example, e.g. with hydrogen in the presence of acatalyst such as palladium/charcoal in a suitable solvent such asmethanol, ethanol, ethyl acetate or glacial acetic acid, optionally withthe addition of an acid such as hydrochloric acid at temperaturesbetween 0 and 100° C., but preferably at ambient temperatures between 20and 60° C., and under a hydrogen pressure of 1 to 7 bar, but preferablyfrom 3 to 5 bar. A 2,4-dimethoxybenzyl group, however, is preferablycleaved in trifluoroacetic acid in the presence of anisole, thioanisole,pentamethylbenzene or triethylsilane.

A tert.-butyl or tert.-butyloxycarbonyl group is preferably cleaved bytreatment with an acid such as trifluoroacetic acid or hydrochloric acidor by treating with iodotrimethylsilane, optionally using a solvent suchas methylene chloride, dioxane, methanol or diethyl ether.

A trifluoroacetyl group is preferably cleaved by treatment with an acidsuch as hydrochloric acid, optionally in the presence of a solvent suchas acetic acid at temperatures between 50 and 120° C. or by treatmentwith sodium hydroxide solution, optionally in the presence of a solventsuch as tetrahydrofuran at temperatures between 0 and 50° C.

Other suitable protective groups and possible ways of introducing andcleaving them are described for example in “Protective Groups in OrganicSynthesis” by Theodora W. Greene and Peter G. M. Wuts, Wiley-VCH, orPhilip Kocienski, Protecting Groups, 3rd ed. 2004, THIEME.

Moreover, the compounds of general formula I obtained may be resolvedinto their enantiomers and/or diastereomers, as mentioned hereinbefore.Thus, for example, cis/trans mixtures may be resolved into their cis andtrans isomers, and compounds with at least one optically active carbonatom may be separated into their enantiomers.

Thus, for example, the cis/trans mixtures obtained may be resolved bychromatography into the cis and trans isomers thereof, the compounds ofgeneral formula I obtained which occur as racemates may be separated bymethods known per se (cf. Allinger N. L. and Eliel E. L. in “Topics inStereochemistry”, Vol. 6, Wiley Interscience, 1971) into their opticalantipodes and compounds of general formula I with at least 2 asymmetriccarbon atoms may be resolved into their diastereomers on the basis oftheir physical-chemical differences using methods known per se, e.g. bychromatography and/or fractional crystallisation, and, if thesecompounds are obtained in racemic form, they may subsequently beresolved into the enantiomers as mentioned above.

The enantiomers are preferably separated by column separation on chiralphases or by recrystallisation from an optically active solvent or byreacting with an optically active substance which forms salts orderivatives such as e.g. esters or amides with the racemic compound,particularly acids and the activated derivatives or alcohols thereof,and separating the diastereomeric mixture of salts or derivatives thusobtained, e.g. on the basis of their differences in solubility, whilstthe free antipodes may be released from the pure diastereomeric salts orderivatives by the action of suitable agents. Optically active acids incommon use are e.g. the D- and L-forms of tartaric acid ordibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelicacid, camphorsulphonic acid, glutamic acid, aspartic acid or quinicacid. An optically active alcohol may be for example (+) or (−)-mentholand an optically active acyl group in amides, for example, may be a (+)-or (−)-menthyloxycarbonyl.

Furthermore, the compounds of formula I obtained may be converted intothe salts thereof, particularly for pharmaceutical use into thephysiologically acceptable salts with inorganic or organic acids orbases. Acids which may be used for this purpose include for examplehydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonicacid, ethanesulphonic acid, benzenesulphonic acid, p-toluenesulphonicacid, phosphoric acid, fumaric acid, succinic acid, benzoic acid,salicylic acid, mandelic acid, lactic acid, malonic acid, citric acid,L-malic acid, L-tartaric acid or maleic acid. Suitable bases for thispurpose include for example sodium hydroxide solution, potassiumhydroxide solution, calcium hydroxide, diethanolamine orN-methyl-D-glucamine.

The compounds of general formulae II to VIII used as starting materialsare known from the literature to some extent or may be obtained bymethods known from the literature (cf. Examples I to IX), optionallywith the additional introduction of protecting groups.

Standard processes for preparing the starting materials are describedfor example in “March's Advanced Organic Chemistry” by Michael B. Smithand Jerry March, Wiley-VCH or in “Science of Synthesis/Houben-Weyl”published by Thieme.

As already mentioned hereinbefore, the compounds of general formula (I)according to the invention and the physiologically acceptable saltsthereof have valuable pharmacological properties, particularly aninhibiting effect on signal transduction mediated by the EpidermalGrowth Factor receptor (EGF-R), whilst this may be achieved for exampleby inhibiting ligand bonding, receptor dimerisation or tyrosine kinaseitself. It is also possible to block the transmission of signals tocomponents located further downstream.

The following Examples are intended to illustrate the present inventionwithout restricting it:

Preparation of the Starting Compounds Example I4-[(3-chloro-2-fluoro-phenyl)amino]-6-(4-oxo-cyclohexyloxy)-7-methoxy-quinazoline

25 ml of 4M sulphuric acid are added to 9.0 g4-[(3-chloro-2-fluoro-phenyl)amino]-6-(1,4-dioxa-spiro[4.5]decan-8-yl-oxy)-7-methoxy-quinazolinein 110 ml of tetrahydrofuran and the mixture is stirred for 18 hours atambient temperature. The mixture is made alkaline with 4M sodiumhydroxide solution and extracted several times with ethyl acetate. Thecombined organic phases are dried, evaporated down and stirred withdiethyl ether. The solid is suction filtered and dried.

Yield: 7.4 g (90% of theory)

Mass spectrum (ESI⁺): m/z=416, 418[M+H]⁺

Example II4-[(3-chloro-2-fluoro-phenyl)amino]-6-(1,4-dioxa-spiro[4.5]decan-8-yl-oxy)-7-methoxy-quinazoline

12.5 g potassium carbonate and 16 g8-methanesulphonyloxy-1,4-dioxa-spiro[4.5]decan (cf. for example Journalof Medicinal Chemistry (1992), 35(12), 2243-7) in 125 mldimethylformamide are added at 50° C. to 18.1 g4-[(3-chloro-2-fluoro-phenyl)amino]-6-hydroxy-7-methoxy-quinazoline (cf.for example Bioorganic & Medicinal Chemistry Letters (2006), 16(18),4908-4912) and the mixture is stirred for 18 hours at 80° C. Another 4.7g potassium carbonate and 4.0 g8-methanesulphonyloxy-1,4-dioxa-spiro[4.5]decan are added and themixture is stirred for a further 7 hours at 80° C. The reaction mixtureis cooled, diluted with water and ethyl acetate and the precipitateformed is suction filtered and dried.

Yield: 12.2 g (47% of theory)

Mass spectrum (ESI⁺): m/z=460, 462[M+H]⁺

Example III4-[(3-chloro-2-fluoro-phenyl)amino]-6-(4-oxo-cyclohexyloxy)-7-methoxy-quinazoline

8.5 ml phosphorus oxychloride are added dropwise to 17 g3,4-dihydro-4-oxo-6-(1,4-dioxa-spiro[4.5]decan-8-yl-oxy)-7-methoxy-quinazolinein 120 ml acetonitrile and the mixture is heated to an internaltemperature of 40° C. Then 13 ml triethylamine are added dropwise andthe reaction mixture is refluxed for 2 hours. The mixture is cooled toambient temperature, combined with 3.6 ml triethylamine and then 7.5 mlof 3-chloro-2-fluoro-5-aniline in 10 ml acetonitrile are added dropwisethereto. The reaction mixture is heated to 40° C. for 5 hours, thencooled and the precipitate is suction filtered. The solid is combinedwith a mixture of 1M hydrochloric acid and 6M isopropanolic hydrochloricacid and stirred for 24 hours. The precipitate is suction filtered,again combined with a mixture of 1M hydrochloric acid and 6Misopropanolic hydrochloric acid and stirred for 6 hours. The precipitateis suction filtered and divided between 1M sodium hydroxide solution anddichloromethane. The organic phase is separated off, dried andevaporated down.

Yield: 17 g (80% of theory)

Mass spectrum (ESI⁺): m/z=416, 418[M+H]⁺

Example IV3,4-dihydro-4-oxo-6-(1,4-dioxa-spiro[4.5]decan-8-yl-oxy)-7-methoxy-quinazoline

16.0 g3-benzyl-3,4-dihydro-4-oxo-6-(1,4-dioxa-spiro[4.5]decan-8-yl-oxy)-7-methoxy-quinazolinein 150 ml glacial acetic acid are hydrogenated in the presence of 1.6 gpalladium on activated charcoal (10% Pd) at 60° C. at a hydrogenpressure of 50 psi. The catalyst is filtered off and the filtrate isevaporated down, combined with toluene and evaporated down again. Theresidue is mixed with water and made slightly alkaline with saturatedsodium hydrogen carbonate solution. The precipitate is suction filteredand dried.

Mass spectrum (ESI⁺): m/z=333[M+H]⁺

Example V3-benzyl-3,4-dihydro-4-oxo-6-(1,4-dioxa-spiro[4.5]decan-8-yl-oxy)-7-methoxy-quinazoline

16.0 g potassium carbonate and 20.0 g8-methanesulphonyloxy-1,4-dioxa-spiro[4.5]decan are added at 50° C. to20.0 g 3-benzyl-3,4-dihydro-4-oxo-6-hydroxy-7-methoxy-quinazoline in 150ml N,N-dimethylformamide and the mixture is vigorously stirred for 18hours at 80° C. To complete the reaction potassium carbonate and8-methanesulphonyloxy-1,4-dioxa-spiro[4.5]decan are each added threetimes and in each case the mixture is stirred for several hours at 80°C. The reaction mixture is cooled and slowly combined with a total of500 ml of water. The precipitate is suction filtered, washed with waterand dried.

Mass spectrum (ESI⁺): m/z=423[M+H]⁺

Example VI 3-benzyl-3,4-dihydro-4-oxo-6-acetyloxy-7-methoxy-quinazoline

169 g 3,4-dihydro-4-oxo-6-acetyloxy-7-methoxy-quinazoline, 118.8 mlbenzylbromide and 138.2 g potassium carbonate are heated to 35-40° C. in1600 ml acetone for 8 hours. The mixture is stirred for 15 hours atambient temperature and then combined with 2000 ml of water. Thesuspension is cooled to 0° C., the precipitate is suction filtered,washed with 400 ml of water and 400 ml tert.-butylmethylether and driedat 50° C. The solid is dissolved in 4000 ml methylene chloride, filteredand evaporated down. The residue is suspended in tert.-butylmethylether,suction filtered and dried at 50° C. Yield: 203 g (86% of theory)

R_(f) value: 0.80 (silica gel, methylene chloride/ethanol=9:1)

Mass spectrum (ESI⁺): m/z=325[M+H]⁺

Example VII 3-benzyl-3,4-dihydro-4-oxo-6-hydroxy-7-methoxy-quinazoline

Method A:

168.5 g 6-hydroxy-7-methoxy-benzo[d][1,3]oxazin-4-one are dissolved in1200 ml of toluene and 74.7 ml benzylamine are added. The mixture isrefluxed for 15 hours and then cooled to ambient temperature. Theprecipitate is filtered off and washed with tert.-butylmethylether.

Yield 124 g (72% of theory)

Method B:

200 g 3-benzyl-3,4-dihydro-4-oxo-6-acetyloxy-7-methoxy-quinazoline aresuspended in 200 ml of water and 1000 ml of ethanol. 300 ml of 10Nsodium hydroxide solution are added at ambient temperature and themixture is heated to 30° C. for 1 hour. After the addition of 172 mlacetic acid and 2000 ml of water the mixture is stirred for 20 hours atambient temperature. The precipitate is suction filtered, washed withwater and acetone and dried at 60° C.

Yield: 172.2 g (98% of theory)

R_(f) value: 0.25 (silica gel, methylene chloride/ethanol=19:1)

Mass spectrum (ESI⁺): m/z=283[M+H]⁺

Example VIII 6-Hydroxy-7-methoxy-benzo[d][1,3]oxazin-4-one

1 g 2-amino-5-hydroxy-4-methoxy-benzoic acid (prepared by reactingmethyl2-nitro-4,5-dimethoxy-benzoate with potassium hydroxide solutionto obtain the 2-nitro-5-hydroxy-4-methoxy-benzoic acid potassium saltand subsequent catalytic hydrogenation in the presence of palladium onactivated charcoal) and 20 ml triethyl orthoformate are heated to 100°C. for 2.5 hours. After cooling to ambient temperature the precipitateis suction filtered and washed with diethyl ether.

Yield: 0.97 g (93% of theory)

R_(f) value: 0.86 (silica gel, methylene chloride/methanol/aceticacid=90:10:1)

Mass spectrum (ESI⁺): m/z=194[M+H]⁺

Example IX4-chloro-6-(1,4-dioxa-spiro[4.5]decan-8-yl-oxy)-7-methoxy-quinazoline

6 ml phosphorus oxychloride are added dropwise to 12.1 g of3,4-dihydro-4-oxo-6-(1,4-dioxa-spiro[4.5]decan-8-yl-oxy)-7-methoxy-quinazolinein 120 ml acetonitrile and the mixture is heated to an internaltemperature of 40° C. Then 9.3 ml triethylamine are added dropwise andthe reaction mixture is refluxed for 3 hours. The mixture is cooled toambient temperature and left to stand overnight. The solution of theproduct is reacted further without purification (see Example III).

Preparation of the End Compounds Example 14-[(3-chloro-2-fluoro-phenyl)amino]-6-[cis-4-(4-ethyl-3-oxo-piperazin-1-yl)-cyclohexyloxy]-7-methoxy-quinazolineand4-[(3-chloro-2-fluoro-phenyl)amino]-6-[trans-4-(4-ethyl-3-oxo-piperazin-1-yl)-cyclohexyloxy]-7-methoxy-quinazoline

1500 mg of4-[(3-chloro-2-fluoro-phenyl)amino]-6-(4-oxo-cyclohexyloxy)-7-methoxy-quinazolinein 50 ml dichloromethane are combined with 555 mg of4-ethyl-3-oxo-piperazine and 250 μl of glacial acetic acid and stirredfor 15 minutes at ambient temperature. Then 1100 mg of sodiumtriacetoxyborohydride are added and the mixture is stirred for 18 hoursat ambient temperature. Some more sodium triacetoxyborohydride is addedand the mixture is stirred for a further 3 hours. The reaction mixtureis combined with dichloromethane and 1M sodium hydroxide solution,briefly stirred and extracted several times with dichloromethane. Thecombined organic phases are dried on magnesium sulphate and evaporateddown. The two title compounds are obtained as a mixture by purificationthrough a silica gel column with ethyl acetate/methanol/aqueous ammonia(95:5:0.1 to 80:20:0.1). The separation of the cis/trans mixture iscarried out by preparative HPLC (xBridge™ C18 made by Waters;acetonitrile, water, aqueous ammonia). The isomers are assigned by1H-NMR spectroscopy (400 MHz, dimethylsulphoxide-d6).

-   4-[(3-chloro-2-fluoro-phenyl)amino]-6-[cis-4-(4-ethyl-3-oxo-piperazin-1-yl)-cyclohexyloxy]-7-methoxy-quinazoline:

Yield: 610 mg (32% of theory)

Mass spectrum (ESI⁺): m/z=528, 530[M+H]⁺

characteristic signal at 4.71 (1H, m)

-   4-[(3-chloro-2-fluoro-phenyl)amino]-6-[trans-4-(4-ethyl-3-oxo-piperazin-1-yl)-cyclohexyloxy]-7-methoxy-quinazoline:

Yield: 520 mg (27% of theory)

Mass spectrum (ESI⁺): m/z=528, 530[M+H]⁺

characteristic signal at 4.45 (1H, m)

The following compounds are obtained analogously to Example 1:

-   (1)    4-[(3-chloro-2-fluoro-phenyl)amino]-6-[cis-4-(4-cyclopropylmethyl-3-oxo-piperazin-1-yl)-cyclohexyloxy]-7-methoxy-quinazoline    and    4-[(3-chloro-2-fluoro-phenyl)amino]-6-[trans-4-(4-cyclopropylmethyl-3-oxo-piperazin-1-yl)-cyclohexyloxy]-7-methoxy-quinazoline

-   4-[(3-chloro-2-fluoro-phenyl)amino]-6-[cis-4-(4-cyclopropylmethyl-3-oxo-piperazin-1-yl)-cyclohexyloxy]-7-methoxy-quinazoline

Mass spectrum (ESI⁺): m/z=554, 556[M+H]⁺

-   4-[(3-chloro-2-fluoro-phenyl)amino]-6-[trans-4-(4-cyclopropylmethyl-3-oxo-piperazin-1-yl)-cyclohexyloxy]-7-methoxy-quinazoline

Mass spectrum (ESI⁺): m/z=554, 556[M+H]⁺

-   (2)    4-[(3-chloro-2-fluoro-phenyl)amino]-6-[cis-4-(4-butyl-3-oxo-piperazin-1-yl)-cyclohexyloxy]-7-methoxy-quinazoline    and    4-[(3-chloro-2-fluoro-phenyl)amino]-6-[trans-4-(4-butyl-3-oxo-piperazin-1-yl)-cyclohexyloxy]-7-methoxy-quinazoline

-   4-[(3-chloro-2-fluoro-phenyl)amino]-6-[cis-4-(4-butyl-3-oxo-piperazin-1-yl)-cyclohexyloxy]-7-methoxy-quinazoline

Mass spectrum (ESI⁺): m/z=556, 558[M+H]⁺

-   4-[(3-chloro-2-fluoro-phenyl)amino]-6-[trans-4-(4-butyl-3-oxo-piperazin-1-yl)-cyclohexyloxy]-7-methoxy-quinazoline

Mass spectrum (ESI⁺): m/z=556, 558[M+H]⁺

-   (3)    4-[(3-chloro-2-fluoro-phenyl)amino]-6-{cis-4-[4-(tetrahydropyran-4-yl)-3-oxo-piperazin-1-yl]-cyclohexyloxy}-7-methoxy-quinazoline    and    4-[(3-chloro-2-fluoro-phenyl)amino]-6-{trans-4-[4-(tetrahydropyran-4-yl)-3-oxo-piperazin-1-yl]-cyclohexyloxy}-7-methoxy-quinazoline

-   4-[(3-chloro-2-fluoro-phenyl)amino]-6-{cis-4-[4-(tetrahydropyran-4-yl)-3-oxo-piperazin-1-yl]-cyclohexyloxy}-7-methoxy-quinazoline

Mass spectrum (ESI⁺): m/z=584, 586[M+H]⁺

-   4-[(3-chloro-2-fluoro-phenyl)amino]-6-{trans-4-[4-(tetrahydropyran-4-yl)-3-oxo-piperazin-1-yl]-cyclohexyloxy}-7-methoxy-quinazoline

Mass spectrum (ESI⁺): m/z=584, 586[M+H]⁺

The following by-products were isolated during this reaction:

-   4-[(3-chloro-2-fluoro-phenyl)amino]-6-(cis-4-hydroxy-cyclohexyloxy)-7-methoxy-quinazoline

Mass spectrum (ESI⁺): m/z=418, 420[M+H]⁺

-   4-[(3-chloro-2-fluoro-phenyl)amino]-6-(trans-4-hydroxy-cyclohexyloxy)-7-methoxy-quinazoline

Mass spectrum (ESI⁺): m/z=418, 420[M+H]⁺

Biological Test

The biological properties of the new compounds are investigated asfollows, for example:

The inhibition of the EGF-R-mediated signal transmission can bedemonstrated e.g. with cells which express human EGF-R and whosesurvival and proliferation depend on stimulation by EGF or TGF-alpha. Amurine haematopoietic cell line is genetically modified so as to expressfunctional human EGF-R. The proliferation of this cell line cantherefore be stimulated by EGF.

The test is carried out as follows:

The cells are cultivated in RPMI/1640 medium. The proliferation isstimulated with 20 ng/ml of human EGF (Promega). To investigate theinhibitory activity of the compounds according to the invention thesecompounds are dissolved in 100% dimethylsulphoxide (DMSO) and added tothe cultures in various dilutions, the maximum DMSO concentration being1%. The cultures are incubated for 48 hours at 37° C.

In order to determine the inhibitory activity of the compounds accordingto the invention the relative cell number is measured in O.D. unitsusing the Cell Titer 96™ AQueous Non-Radioactive Cell ProliferationAssay (Promega). The relative cell number is calculated as a percentageof the control and the concentration of active substance which inhibitsthe proliferation of the cells by 50% (IC50) is derived therefrom.

The compounds of general formula (I) according to the invention exhibitIC50 values of <10 micromolar, preferably <1 micromolar, for example.

Inhibition of EGFR-dependent Compound (Example No.) proliferation IC₅₀[nM] 1, cis 7.1 1, trans 1.3 1(1), cis 10.1 1(1), trans 1.7 1(2), cis12.1 1(2), trans 3.1 1(3), cis 9.3 1(3), trans 1.6Indications

As has been found, the compounds of formula (I) are characterised inthat by their versatility in the therapeutic field. Particular mentionshould be made of the possible applications for which the compounds offormula (I) according to the invention are preferably used on the basisof their pharmaceutical efficacy as tyrosine inhibitors.

The compounds of general formula (I) according to the invention thusinhibit signal transduction by tyrosine kinases, as demonstrated by theexample of the human EGF receptor, and are therefore useful for treatingpathophysiological processes caused by hyperfunction of tyrosinekinases. These are e.g. benign or malignant tumours, particularlytumours of epithelial and neuroepithelial origin, metastasisation andthe abnormal proliferation of vascular endothelial cells(neoangiogenesis).

The compounds according to the invention are also useful for preventingand treating diseases of the airways and lungs which are accompanied byincreased or altered production of mucus caused by stimulation oftyrosine kinases, e.g. in inflammatory diseases of the airways such aschronic bronchitis, chronic obstructive bronchitis, asthma,bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cysticfibrosis, α1-antitrypsin deficiency, or coughs, pulmonary emphysema,pulmonary fibrosis and hyperreactive airways.

The compounds are also suitable for treating diseases of thegastrointestinal tract and bile duct and gall bladder which areassociated with disrupted activity of the tyrosine kinases, such as maybe found e.g. in chronic inflammatory changes such as cholecystitis,Crohn's disease, ulcerative colitis, and ulcers in the gastrointestinaltract or such as may occur in diseases of the gastrointestinal tractwhich are associated with increased secretions, such as Ménétrier'sdisease, secreting adenomas and protein loss syndrome.

In addition, the compounds of general formula I and the physiologicallyacceptable salts thereof may be used to treat other diseases caused byabnormal function of tyrosine kinases, such as e.g. epidermalhyperproliferation (psoriasis), benign prostatic hyperplasia (BPH),inflammatory processes, diseases of the immune system,hyperproliferation of haematopoietic cells, the treatment of nasalpolyps, etc.

By reason of their biological properties the compounds according to theinvention may be used on their own or in conjunction with otherpharmacologically active compounds, for example in tumour therapy, inmonotherapy or in conjunction with other anti-tumour therapeutic agents,for example in combination with topoisomerase inhibitors (e.g.etoposide), mitosis inhibitors (e.g. vinblastine), compounds whichinteract with nucleic acids (e.g. cis-platin, cyclophosphamide,adriamycin), hormone antagonists (e.g. tamoxifen), inhibitors ofmetabolic processes (e.g. 5-FU etc.), cytokines (e.g. interferons),antibodies, etc. For treating respiratory tract diseases, thesecompounds may be used on their own or in conjunction with othertherapeutic agents for the airways, such as substances with asecretolytic (e.g. ambroxol, N-acetylcysteine), broncholytic (e.g.tiotropium or ipratropium or fenoterol, salmeterol, salbutamol) and/oranti-inflammatory activity (e.g. theophylline or glucocorticoids). Fortreating diseases in the region of the gastrointestinal tract, thesecompounds may also be administered on their own or in conjunction withsubstances having an effect on motility or secretion. These combinationsmay be administered either simultaneously or sequentially.

Formulations

The compounds according to the invention may be administered by oral,transdermal, inhalative, parenteral or sublingual route. The compoundsaccording to the invention are present as active ingredients inconventional preparations, for example in compositions consistingessentially of an inert pharmaceutical carrier and an effective dose ofthe active substance, such as for example tablets, coated tablets,capsules, lozenges, powders, solutions, suspensions, emulsions, syrups,suppositories, transdermal systems etc. An effective dose of thecompounds according to the invention is between 0.1 and 5000, preferablybetween 1 and 500, more preferably between 5-300 mg/dose for oraladministration, and between 0.001 and 50, preferably between 0.1 and 10mg/dose for intravenous, subcutaneous or intramuscular administration.For inhalation, according to the invention, solutions containing 0.01 to1.0, preferably 0.1 to 0.5% active substance are suitable. Foradministration by inhalation the use of powders, ethanolic or aqueoussolutions is preferred. It is also possible to use the compoundsaccording to the invention as a solution for infusion, preferably in aphysiological saline or nutrient saline solution.

The compounds according to the invention may be used on their own or inconjunction with other active substances according to the invention,optionally also in conjunction with other pharmacologically activesubstances. Suitable formulations include, for example, tablets,capsules, suppositories, solutions, syrups, emulsions or dispersiblepowders. Corresponding tablets may be obtained for example by mixing theactive substance(s) with known excipients, for example inert diluents,such as calcium carbonate, calcium phosphate or lactose, disintegrantssuch as maize starch or alginic acid, binders such as starch orgelatine, lubricants such as magnesium stearate or talc and/or agentsfor delaying release, such as carboxymethyl cellulose, cellulose acetatephthalate, or polyvinyl acetate. The tablets may also comprise severallayers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example collidone or shellac, gum arabic, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number of layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups containing the active substances or combinations thereofaccording to the invention may additionally contain a sweetener such assaccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. aflavouring such as vanillin or orange extract. They may also containsuspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Solutions for injection are prepared in the usual way, e.g. with theaddition of preservatives such as p-hydroxybenzoates, or stabiliserssuch as alkali metal salts of ethylenediamine tetraacetic acid, andtransferred into injection vials or ampoules.

Capsules containing one or more active substances or combinations ofactive substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriersprovided for this purpose, such as neutral fats or polyethyleneglycol orthe derivatives thereof.

For pharmaceutical use the compounds according to the invention aregenerally used for warm-blooded vertebrates, particularly humans, indoses of 0.01-100 mg/kg of body weight, preferably 0.1-15 mg/kg. Foradministration they are formulated with one or more conventional inertcarriers and/or diluents, e.g. with corn starch, lactose, glucose,microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone,citric acid, tartaric acid, water, water/ethanol, water/glycerol,water/sorbitol, water/polyethylene glycol, propylene glycol, stearylalcohol, carboxymethylcellulose or fatty substances such as hard fat orsuitable mixtures thereof to produce conventional galenic preparationssuch as plain or coated tablets, capsules, powders, suspensions,solutions, sprays or suppositories.

The Examples which follow illustrate the present invention withoutrestricting its scope:

Examples of Pharmaceutical Formulations

A) Coated Tablets Containing 75 mg of Active Substance

Composition:

1 tablet core contains: active substance 75.0 mg calcium phosphate 93.0mg corn starch 35.5 mg polyvinylpyrrolidone 10.0 mghydroxypropylmethylcellulose 15.0 mg magnesium stearate  1.5 mg 230.0mg Preparation:

The active substance is mixed with calcium phosphate, corn starch,polyvinyl-pyrrolidone, hydroxypropylmethylcellulose and half thespecified amount of magnesium stearate. Blanks 13 mm in diameter areproduced in a tablet-making machine and these are then rubbed through ascreen with a mesh size of 1.5 mm using a suitable machine and mixedwith the rest of the magnesium stearate. This granulate is compressed ina tablet-making machine to form tablets of the desired shape.

-   -   Weight of core: 230 mg    -   die: 9 mm, convex

The tablet cores thus produced are coated with a film consistingessentially of hydroxypropylmethylcellulose. The finished film-coatedtablets are polished with beeswax.

-   -   Weight of coated tablet: 245 mg.        B) Tablets Containing 100 mg of Active Substance        Composition:

1 tablet contains: active substance 100.0 mg lactose 80.0 mg corn starch34.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 2.0 mg 220.0 mgMethod of Preparation:

The active substance, lactose and starch are mixed together anduniformly moistened with an aqueous solution of thepolyvinylpyrrolidone. After the moist composition has been screened (2.0mm mesh size) and dried in a rack-type drier at 50° C. it is screenedagain (1.5 mm mesh size) and the lubricant is added. The finishedmixture is compressed to form tablets.

-   -   Weight of tablet: 220 mg    -   Diameter: 10 mm, biplanar, facetted on both sides and notched on        one side.        C) Tablets Containing 150 mg of Active Substance        Composition:

1 tablet contains: active substance 150.0 mg powdered lactose 89.0 mgcorn starch 40.0 mg colloidal silica 10.0 mg polyvinylpyrrolidone 10.0mg magnesium stearate 1.0 mg 300.0 mgPreparation:

The active substance mixed with lactose, corn starch and silica ismoistened with a 20% aqueous polyvinylpyrrolidone solution and passedthrough a screen with a mesh size of 1.5 mm. The granules, dried at 45°C., are passed through the same screen again and mixed with thespecified amount of magnesium stearate. Tablets are pressed from themixture.

-   -   Weight of tablet: 300 mg    -   die: 10 mm, flat        D) Hard Gelatine Capsules Containing 150 mg of Active Substance        Composition:

1 capsule contains: active substance 150.0 mg corn starch (dried)approx. 180.0 mg lactose (powdered) approx. 87.0 mg magnesium stearate3.0 mg approx. 420.0 mgPreparation:

The active substance is mixed with the excipients, passed through ascreen with a mesh size of 0.75 mm and homogeneously mixed using asuitable apparatus. The finished mixture is packed into size 1 hardgelatine capsules.

-   -   Capsule filling: approx. 320 mg    -   Capsule shell: size 1 hard gelatine capsule.        E) Suppositories Containing 150 mg of Active Substance        Composition:

1 suppository contains: active substance 150.0 mg polyethyleneglycol1500 550.0 mg polyethyleneglycol 6000 460.0 mg polyoxyethylene sorbitanmonostearate 840.0 mg 2,000.0 mg  Preparation:

After the suppository mass has been melted the active substance ishomogeneously distributed therein and the melt is poured into chilledmoulds.

F) Suspension Containing 50 mg of Active Substance

Composition:

100 ml of suspension contain: active substance 1.00 gcarboxymethylcellulose-Na-salt 0.10 g methyl p-hydroxybenzoate 0.05 gpropyl p-hydroxybenzoate 0.01 g glucose 10.00 g glycerol 5.00 g 70%sorbitol solution 20.00 g flavouring 0.30 g dist. water ad 100 mlPreparation:

The distilled water is heated to 70° C. The methyl and propylp-hydroxybenzoates together with the glycerol and sodium salt ofcarboxymethylcellulose are dissolved therein with stirring. The solutionis cooled to ambient temperature and the active substance is added andhomogeneously dispersed therein with stirring. After the sugar, thesorbitol solution and the flavouring have been added and dissolved, thesuspension is evacuated with stirring to eliminate air.

-   -   5 ml of suspension contain 50 mg of active substance.        G) Ampoules Containing 10 mg Active Substance        Composition:

active substance 10.0 mg 0.01N hydrochloric acid q.s. double-distilledwater ad 2.0 mlPreparation:

The active substance is dissolved in the necessary amount of 0.01 N HCl,made isotonic with common salt, filtered sterile and transferred into 2ml ampoules.

H) Ampoules Containing 50 mg of Active Substance

Composition:

active substance 50.0 mg 0.01N hydrochloric acid q.s. double-distilledwater ad 10.0 mlPreparation:

The active substance is dissolved in the necessary amount of 0.01 N HCl,made isotonic with common salt, filtered sterile and transferred into 10ml ampoules.

I) Capsules for Powder Inhalation Containing 5 mg of Active Substance

1 capsule contains: active substance  5.0 mg lactose for inhalation 15.0mg 20.0 mgPreparation:

The active substance is mixed with lactose for inhalation. The mixtureis packed into capsules in a capsule-making machine (weight of the emptycapsule approx. 50 mg).

weight of capsule: 70.0 mg

size of capsule: 3

J) Solution for Inhalation for Hand-Held Nebulisers Containing 2.5 mgActive Substance

1 spray contains: active substance 2.500 mg benzalkonium chloride 0.001mg 1N hydrochloric acid q.s. ethanol/water (50/50) ad 15.000 mgPreparation:

The active substance and benzalkonium chloride are dissolved inethanol/water (50/50). The pH of the solution is adjusted with 1Nhydrochloric acid. The resulting solution is filtered and transferredinto suitable containers for use in hand-held nebulisers (cartridges).

Contents of the container: 4.5 g

1. A compound of formula (I)

wherein: R^(a) denotes an ethyl, propyl, butyl, cyclopropyl,cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, 3-tetrahydrofuranyl,tetrahydrofuranylmethyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl- andtetrahydropyranylmethyl group, and wherein, unless stated otherwise, theabove-mentioned alkyl groups may be straight-chain or branched,optionally in the form of the tautomers, the racemates, the enantiomers,the diastereomers and the mixtures thereof, and optionally thepharmacologically acceptable acid addition salts thereof.
 2. Thecompound according to claim 1, wherein: R^(a) denotes a group selectedfrom among ethyl, butyl, cyclopropylmethyl and 4-tetrahydropyranylgroup, optionally in the form of the tautomers, the racemates, theenantiomers, the diastereomers and the mixtures thereof, and optionallythe pharmacologically acceptable acid addition salts thereof.
 3. Apharmaceutical formulation containing a compound of formula (I)according to claim
 1. 4. An orally administered pharmaceuticalformulation according to claim 3 containing a compound of formula (I)according to claim 1.